Exposure of the human population to cancer-causing substances in the environment constitutes an important hazard to human health. Among these chemicals are polycyclic aromatic hydrocarbons in urban polluted environments and in cigarette smoke, and aromatic amines mutagens present in cooked foods. These chemicals, once they enter the human body, are activated to highly reactive intermediates that chemically bind to DNA, thus generating bulky adducts. The latter, if not removed by cellular defense mechanisms, can cause mutations and cancer. One of the critical lines of defense of the human body to these environmental carcinogens is DNA repair, specifically by the nucleotide excision repair (NER) mechanism that deals with bulky DNA damage. Unfortunately, the molecule basis of this critical defense mechanism, especially its efficiency in removing important, structurally different DNA lesions, is still obscure. In this project, a systematic approach towards solving this problem is proposed that will identify the kind of carcinogen-DNA lesions that are poorly repaired by NER mechanisms. This information will be useful in biomarker studies of environmental human exposure, and will be especially useful for identifying individuals who, because of genetic polymorphisms, are of particular risk of developing cancer. Such individuals can then be selected for closer monitoring to prevent the development of this disease into tits later life-threatening stages.